p53 impairs endothelial function by transcriptionally repressing Kruppel-Like Factor 2

Ajay Kumar; Cuk-Seong Kim; Timothy A Hoffman; Asma Naqvi; Jeremy Dericco; Saet-Byel Jung; Zhiyong Lin; Mukesh K Jain; Kaikobad Irani

doi:10.1161/ATVBAHA.110.215061

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p53 impairs endothelial function by transcriptionally repressing Kruppel-Like Factor 2

Journal article

Open access

Peer reviewed

p53 impairs endothelial function by transcriptionally repressing Kruppel-Like Factor 2

Ajay Kumar, Cuk-Seong Kim, Timothy A Hoffman, Asma Naqvi, Jeremy Dericco, Saet-Byel Jung, Zhiyong Lin, Mukesh K Jain and Kaikobad Irani

Arteriosclerosis, thrombosis, and vascular biology, Vol.31(1), pp.133-141

01/2011

DOI: 10.1161/ATVBAHA.110.215061

PMCID: PMC3064482

PMID: 20947822

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Abstract

To evaluate if p53 decreases Kruppel-Like Factor 2 (KLF2) expression and determine whether p53-mediated suppression of KLF2 plays a role in p53-induced endothelial dysfunction. Endothelial KLF2 mediates endothelium-dependent vascular homeostasis by differentially regulating endothelial genes, leading to an anti-inflammatory and antithrombotic endothelial surface with normal vasodilatory function. In contrast, the tumor suppressor p53 leads to inflammatory gene expression and impairs endothelium-dependent vasodilatation, thus promoting endothelial dysfunction. The effect of p53 on KLF2 expression was determined. p53 inhibited KLF2 transcription in a histone deacetylase-dependent and a histone acetyltransferase-independent fashion. KLF2 expression was suppressed by p53 via a conserved p53-binding repressor sequence in its promoter. p53 bound to, and stimulated, deacetylation of Histone H3 at the KLF2 promoter. The effect of p53 on endothelial KLF2 target genes was examined. Downregulation of p53 increased expression of endothelial NO synthase and thrombomodulin and inhibited expression of plasminogen activator inhibitor 1. Conversely, overexpression of p53 suppressed endothelial NO synthase and thrombomodulin expression and stimulated plasminogen activator inhibitor 1 and endothelin-1 expression. Knockdown of KLF2 abolished the p53-induced decrease in thrombomodulin and increase in endothelin-1. Both, overexpression of p53 and knockdown of KLF2 in endothelial cells increased blood coagulation on an endothelial cell monolayer. The p53-induced increase in coagulation was rescued by forced expression of KLF2. p53 also impaired endothelium-dependent vasodilatation and decreased bioavailable vascular NO, both of which were rescued by forced KLF2 expression. These findings illustrate a novel p53-dependent mechanism for the regulation of endothelial KLF2 expression. In addition, they show that downregulation of KLF2, in part, mediates a p53-stimulated dysfunctional endothelium.

Humans

Rats, Inbred WKY

Endothelium, Vascular - drug effects

Tumor Suppressor Protein p53 - genetics

Vasodilation

Dose-Response Relationship, Drug

Thrombomodulin - metabolism

Transfection

Plasminogen Activator Inhibitor 1 - metabolism

RNA Interference

Kruppel-Like Transcription Factors - metabolism

Histone Acetyltransferases - metabolism

Blood Coagulation

Transcription, Genetic

Nitric Oxide Synthase Type III - metabolism

Plasminogen Activator Inhibitor 1 - genetics

Thrombomodulin - genetics

Binding Sites

Promoter Regions, Genetic

Vasodilator Agents - pharmacology

Response Elements

Endothelial Cells - metabolism

Endothelin-1 - genetics

Endothelin-1 - metabolism

Down-Regulation

Cells, Cultured

Endothelium, Vascular - physiopathology

Gene Expression Regulation

Tumor Suppressor Protein p53 - metabolism

Chromatin Assembly and Disassembly

Rats

Histone Deacetylases - metabolism

Nitric Oxide Synthase Type III - genetics

Animals

Endothelium, Vascular - metabolism

Histones - metabolism

Nitric Oxide - metabolism

Kruppel-Like Transcription Factors - genetics

Endothelial Cells - drug effects

Details

Title: Subtitle: p53 impairs endothelial function by transcriptionally repressing Kruppel-Like Factor 2
Creators: Ajay Kumar - University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. Kumara@upmc.edu
Cuk-Seong Kim
Timothy A Hoffman
Asma Naqvi
Jeremy Dericco
Saet-Byel Jung
Zhiyong Lin
Mukesh K Jain
Kaikobad Irani
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.31(1), pp.133-141
DOI: 10.1161/ATVBAHA.110.215061
PMID: 20947822
PMCID: PMC3064482
NLM abbreviation: Arterioscler Thromb Vasc Biol
ISSN: 1079-5642
eISSN: 1524-4636
Publisher: United States
Grant note: R56 HL070929-07 / NHLBI NIH HHS R01 HL094959 / NHLBI NIH HHS R01 HL097593 / NHLBI NIH HHS R21 HL098892 / NHLBI NIH HHS HL094959 / NHLBI NIH HHS R01 HL070929 / NHLBI NIH HHS K99 HL087595 / NHLBI NIH HHS P01 HL065608 / NHLBI NIH HHS R21 HL098892-01A1 / NHLBI NIH HHS HL076754 / NHLBI NIH HHS R01 HL086548 / NHLBI NIH HHS R01 HL076754 / NHLBI NIH HHS R01 HL094959-02 / NHLBI NIH HHS HL070929 / NHLBI NIH HHS HL065608 / NHLBI NIH HHS R56 HL070929 / NHLBI NIH HHS HL098892 / NHLBI NIH HHS R01 HL070929-10 / NHLBI NIH HHS HL097593 / NHLBI NIH HHS R00 HL087595 / NHLBI NIH HHS HL087595 / NHLBI NIH HHS
Language: English
Date published: 01/2011
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047995102771

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